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Human Amniotic Epithelial Cells Alleviate a Mouse Model of Parkinson’s Disease Mainly by Neuroprotective, Anti-Oxidative and Anti-Inflammatory Factors

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Abstract

Human amniotic epithelial cells (hAECs) have been reported to have neuroprotective roles in Parkinson’s disease (PD) animal models. However, the molecular mechanism is not fully understood. The present study was designed to explore the possible mechanism by which hAECs ameliorate PD symptoms and the important paracrine factors produced by hAECs that attribute to the recovery of dopaminergic neurons. Thus, we performed in vivo and in vitro experiments with hAECs in PD models or lesioned dopaminergic neurons, respectively. First, hAECs were transplanted into the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice and motor deficits were significantly attenuated. Second, the grafts prevented the loss of nigral dopaminergic neurons and promoted the outgrowth of neurites and striatal axon fibers in PD mice. In addition, decreased microglial activation, inflammatory factor levels and MPTP-induced excessive reactive oxygen species (ROS) levels were also observed in hAEC-treated PD mice. In vitro, we found that the conditioned medium (CM) from hAECs promoted the survival of mesencephalic dopaminergic neurons stimulated with 1-methyl-4-phenylpyridine (MPP+) and induced neurite outgrowth. Next, analysis of hAEC-CM with an antibody array of 507 soluble target proteins revealed that the levels of many neurotrophic factors, growth factors, neuronal cell adhesion molecule (NrCAM) and anti-inflammatory factors were evidently high. In addition, antibody neutralization experiments showed that many of these factors contributed to the survival and growth of dopaminergic neurons and neurite outgrowth. More importantly, we found that the anti-inflammatory factor interleukin-1 receptor antagonist (IL-1ra) also augmented the survival of dopaminergic neurons, demonstrating for the first time an anti-oxidative and anti-inflammatory role of hAECs in PD mice, which represents a novel molecular mechanism of hAECs in the treatment of PD.

The molecular mechanism of hAECs recovering lesioned dopaminergic neurons and attenuating PD symptoms. First, hAECs secret many neurotrophic factors, growth factors, and neuronal cell adhesion molecule (NrCAM) which promote the growth of the damaged dopaminergic neurons and their neurites. Second, hAECs produce many anti-inflammatory factors and other factors contributing to reducing the activation of microglia and suppressing the neuroinflammation. Third, hAECs reduce the excessive ROS levels by upregulating some anti-oxidative signals

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Abbreviations

hAECs:

human amniotic epithelial cells

PD:

Parkinson’s Disease

MPTP:

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

ROS:

reactive oxidative species

NrCAM:

neuronal cell adhesion molecule

SN:

substantia nigra

SNpc:

substantia nigra pars compacta

TH:

tyrosine hydroxylase

H2-DCFDA:

2′,7′-dichlorodihydrofluorescein diacetate

hEF:

adult foreskin fibroblasts

CM:

conditioned medium

CNTF:

Ciliary neurotrophic factor

OSM:

oncostatin M

GM-CSF:

granulocyte-macrophage colony stimulating factor

IL-1ra:

 interleukin-1 receptor antagonist

Nrf2:

nuclear factor erythroid 2-related factor 2

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Acknowledgements

This study was supported by funds from the National Natural Science Foundation of China (31571399 to H. Xu, 81630073 and 81372189 to WQG), the Chinese Ministry of Science and Technology (2017YFA0102900 to WQG), KC Wong foundation to WQG.

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Authors and Affiliations

  1. State Key Laboratory of Oncogenes and Related Genes, Renji-MedX Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, 200127, Shanghai, China

    Jiaofei Zhang, Hui Li, Wei-Qiang Gao & Huiming Xu

  2. Institute of Reproduction and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, 410078, China

    Jiaofei Zhang & Qianjun Zhang

  3. Translational Medicine Center, Honghui Hospital, Xian Jiao Tong University, Xian, 710054, China

    Hao Yang

  4. Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China

    Jianhua Lin & You Wang

  5. Med-X Research Institute and School of Biological Medical Engineering, Shanghai Jiao Tong University, 1594 Huashan Road, Shanghai, 200030, China

    Wei-Qiang Gao

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  1. Jiaofei Zhang
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  2. Hui Li
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Contributions

J.H.Zhang: conception and design, collection/assembly of data, data analysis and interpretation, manuscript writing; H.Yang: design, data analysis and interpretation, and final approval of manuscript. J.H.Lin and Y.Wang: collection and delivery of study material. Q.J.Zhang: conception and design, and final approval of manuscript; W.Q.Gao and H.M.Xu: conception and design, financial support, manuscript writing and final approval of manuscript.

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Correspondence to Qianjun Zhang, Wei-Qiang Gao or Huiming Xu.

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The study was approved by the human and animal Research Ethics Committee of Renji hospital, School of medicine, Shanghai Jiaotong University. Written informed consent was obtained from individual participants.

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Zhang, J., Li, H., Yang, H. et al. Human Amniotic Epithelial Cells Alleviate a Mouse Model of Parkinson’s Disease Mainly by Neuroprotective, Anti-Oxidative and Anti-Inflammatory Factors. J Neuroimmune Pharmacol 16, 620–633 (2021). https://doi.org/10.1007/s11481-020-09969-w

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